Mutation-Adjusted Risk Score (MARS) for Advanced Systemic Mastocytosis

Why use it

KIT D816V mutation alone fails to distinguish the markedly heterogeneous prognosis within AdvSM. S/A/R mutations (SRSF2, ASXL1, RUNX1) are the strongest independent prognostic factors in AdvSM, identifying a high-risk subgroup with short median OS (~3–11 months) that requires aggressive treatment. MARS provides a practical, reproducible score combining molecular and clinical variables to stratify prognosis, guide treatment intensity, and support shared decision-making. It complements the GIPSS score and the International Prognostic Scoring System for Mastocytosis (IPS-M).

About

The Mutation-Adjusted Risk Score (MARS) is a validated prognostic scoring system for advanced systemic mastocytosis (AdvSM), developed by Jawhar and colleagues and published in Blood in 2019. AdvSM encompasses aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL) — a spectrum of diseases characterized by neoplastic mast cell infiltration of visceral organs, often with life-threatening end-organ damage. MARS incorporates four variables: (1) the presence of at least one of three co-occurring somatic mutations in SRSF2, ASXL1, or RUNX1 (collectively termed S/A/R mutations), which are present in approximately 60–70% of AdvSM patients and confer significantly inferior outcomes; (2) hemoglobin below 11 g/dL; (3) platelet count below 100 × 10⁹/L; and (4) alkaline phosphatase at or above 100 U/L. S/A/R mutations are assessed by targeted next-generation sequencing and represent co-occurring mutations beyond the near-universal KIT D816V driver mutation. MARS stratifies AdvSM patients into three prognostic groups with markedly different median overall survival (OS) outcomes. The score is used to guide treatment intensity — particularly decisions about KIT D816V inhibitor therapy (midostaurin, avapritinib), allogeneic stem cell transplantation, and clinical trial eligibility.

When to use

• Initial prognostic stratification at diagnosis of advanced systemic mastocytosis (ASM, SM-AHN, or MCL)
• Before initiating KIT inhibitor therapy (midostaurin or avapritinib) to contextualize expected response based on mutation profile
• Evaluating eligibility for allogeneic hematopoietic stem cell transplantation — high MARS score supports early transplant consideration
• Clinical trial enrollment and stratification in AdvSM studies
• Serial assessment after treatment to monitor disease evolution and response
• Multidisciplinary hematology-oncology case reviews for AdvSM patients

Formula

Pearls & pitfalls

• S/A/R mutations (SRSF2, ASXL1, RUNX1) are co-occurring mutations BEYOND the KIT D816V driver mutation — they are assessed by separate next-generation sequencing panels (not by the allele-specific PCR used for KIT D816V).
• The presence of even ONE S/A/R mutation contributes 2 points (the maximum single-variable weight) in MARS, reflecting their dominant prognostic impact.
• KIT D816V alone does NOT discriminate prognosis in AdvSM — virtually all AdvSM patients carry KIT D816V; MARS adds the molecular context that distinguishes outcomes.
• Avapritinib (Blueprint Medicines) is a potent, selective KIT D816V inhibitor approved for AdvSM — it produces deep molecular and histological responses, especially in patients without S/A/R mutations (MARS low risk).
• S/A/R mutations are associated with higher WHO classification (MCL > ASM) and SM-AHN, reflecting clonal evolution from an earlier myeloid neoplasm.
• Thrombocytopenia (<100 × 10⁹/L) in AdvSM often results from both mast cell infiltration of marrow and SM-AHN-related hematopoietic failure — it is a critical prognostic marker.
• Serum alkaline phosphatase (ALP) elevation in AdvSM primarily reflects hepatic mast cell infiltration (not bone disease) — it is a surrogate for systemic organ involvement.
• MARS was derived from a multicenter European cohort and validated in an independent cohort — the three risk groups showed non-overlapping survival curves, supporting clinical utility.
• Allogeneic stem cell transplantation (allo-SCT) remains the only potentially curative therapy for AdvSM — it should be considered early in MARS intermediate/high-risk patients who are fit.
• The WHO 2022 classification introduced a new category — mast cell sarcoma — distinct from MCL, and the applicability of MARS to this entity is not established.

Next steps

MARS Low Risk (0–1): Median OS not reached (>60 months in published series). Close monitoring with WHO diagnostic workup including bone marrow biopsy, serum tryptase, and KIT D816V quantification. Assess eligibility for KIT inhibitor therapy based on symptom burden and organ damage. Re-evaluate every 3–6 months. MARS Intermediate Risk (2–3): Median OS ~11 months. Consider early initiation of KIT D816V inhibitor therapy (avapritinib preferred; midostaurin as alternative). Evaluate for allogeneic stem cell transplantation in eligible patients with SM-AHN. Frequent monitoring (every 1–3 months). MARS High Risk (4–5): Median OS ~3 months. Urgent consideration of KIT inhibitor therapy — avapritinib 200–300 mg/day for AdvSM. Urgent stem cell transplant referral in fit candidates. Clinical trial enrollment strongly encouraged. Optimize supportive care and anti-mediator therapy.

Evidence

Jawhar M et al. Molecular profiling of myeloid progenitor cells in multi-mutation systemic mastocytosis identifies early origins and mast cell bias. Blood. 2019;134(2):137-148. PMID:31101620. MARS derivation cohort: 93 patients. Median OS: low (0–1) NR, intermediate (2–3) 11.0 months, high (4–5) 3.4 months (p<0.001). Multi-center validation confirms three distinct prognostic groups. Cross-referenced with GIPSS (Genetic and Morphological Parameters Scoring System). Naumann N et al. Presence of additional mutations determines the prognosis of systemic mastocytosis. J Allergy Clin Immunol. 2018. Reiter A et al. Systemic mastocytosis: updates in diagnosis and management. Blood. 2020.

References

1. Jawhar M et al. Molecular profiling of myeloid progenitor cells in multi-mutation systemic mastocytosis. Blood. 2019;134(2):137-148. — link
2. Reiter A et al. Systemic mastocytosis — updates in diagnosis and management. Blood. 2020;135(16):1365-1376. — link
3. Gotlib J et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016;374(26):2530-2541. — link
4. Deangelo DJ et al. Avapritinib for Advanced Systemic Mastocytosis. N Engl J Med. 2021;384(14):1307-1316. — link
5. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 5th Edition. Lyon: IARC; 2022. — link